Circulating Sex-Specific Markers of Plaque Instability in Women and Men With Severe Carotid Atherosclerosis.

BACKGROUND: Sex-specific differences in plaque composition and instability underscore the need to explore circulating markers for better prediction of high-risk plaques. This cross-sectional study aims to (1) investigate differences in lipid, immune, and adipokine circulating profiles between men and women with stable versus unstable plaques and (2) identify circulating markers that can better classify men and women according to plaque instability. METHODS: Preoperative blood samples and plaque specimens were collected from consecutive men and women with carotid artery stenosis ≥50% and who underwent a carotid endarterectomy between 2009 and 2018. Adipokine, lipid, and immune profiling was conducted. Plaque stability was determined by gold-standard histological classifications. Statistical analyses, including χ2, ANOVA, Kruskal-Wallis, and logistic regression, assessed differences in plaque features and blood parameters between men and women with stable and unstable plaques. RESULTS: Of 470 recruited patients (aged 70.8±9.2 years), the final study analyses included 317 men and 143 women (aged 71.0±9.0 years). Men exhibited more unstable plaques (P<0.001), characterized by increased plaque hemorrhage, larger lipid core, and inflammation (P<0.001), along with less favorable circulating profiles. Antagonistic interactions between sex and white blood cell (WBC) counts, basophil-to-WBC ratio, and platelet counts influenced plaque instability. In men, low WBC counts, high monocyte-to-WBC ratio, low basophil-to-WBC ratio, and high LDL-C (low-density lipoprotein cholesterol) levels were associated with greater plaque instability (odds ratio, 0.827 [95% CI, 0.713-0.926], 1.158 [95% CI, 1.027-1.305], 0.495 [95% CI, 0.281-0.871], and 1.564 [95% CI, 1.001-2.443], respectively) and more unstable features (ie, inflammation, foam cells, and neovascularization). In women, a high basophil-to-WBC ratio was associated with greater plaque instability (3.142 [95% CI, 1.220-8.093]), hemorrhage, and thrombosis, while a high molecular weight-to-total adiponectin ratio was associated with decreased instability (0.014 [95% CI, 0.000-0.646]) and inflammation. CONCLUSIONS: Our findings demonstrated sex-specific differences, with women displaying more stable plaque phenotypes and favorable circulating profiles compared with men. This proof-of-concept study was also designed as the key first step in exploring novel sex-specific associations between circulating lipid, immune, and adipokine profiles and carotid plaque instability.

Macrophage profiling in atherosclerosis: understanding the unstable plaque.

The development and rupture of atherosclerotic plaques is a major contributor to myocardial infarctions and ischemic strokes. The dynamic evolution of the plaque is largely attributed to monocyte/macrophage functions, which respond to various stimuli in the plaque microenvironment. To this end, macrophages play a central role in atherosclerotic lesions through the uptake of oxidized low-density lipoprotein that gets trapped in the artery wall, and the induction of an inflammatory response that can differentially affect the stability of the plaque in men and women. In this environment, macrophages can polarize towards pro-inflammatory M1 or anti-inflammatory M2 phenotypes, which represent the extremes of the polarization spectrum that include Mhem, M(Hb), Mox, and M4 populations. However, this traditional macrophage model paradigm has been redefined to include numerous immune and nonimmune cell clusters based on in-depth unbiased single-cell approaches. The goal of this review is to highlight (1) the phenotypic and functional properties of monocyte subsets in the circulation, and macrophage populations in atherosclerotic plaques, as well as their contribution towards stable or unstable phenotypes in men and women, and (2) single-cell RNA sequencing studies that have advanced our knowledge of immune, particularly macrophage signatures present in the atherosclerotic niche. We discuss the importance of performing high-dimensional approaches to facilitate the development of novel sex-specific immunotherapies that aim to reduce the risk of cardiovascular events.

Diabetes, antidiabetic medications and risk of dementia: A systematic umbrella review and meta-analysis.

AIMS: The objective of this umbrella review and meta-analysis was to evaluate the effect of diabetes on risk of dementia, as well as the mitigating effect of antidiabetic treatments. MATERIALS AND METHODS: We conducted a systematic umbrella review on diabetes and its treatment, and a meta-analysis focusing on treatment. We searched MEDLINE/PubMed, Embase, PsycINFO, CINAHL and the Cochrane Library for systematic reviews and meta-analyses assessing the risk of cognitive decline/dementia in individuals with diabetes until 2 July 2023. We conducted random-effects meta-analyses to obtain risk ratios and 95% confidence intervals estimating the association of metformin, thiazolidinediones, pioglitazone, dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors, meglitinides, insulin, sulphonylureas, glucagon-like peptide-1 receptor agonists (GLP1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) with risk of dementia from cohort/case-control studies. The subgroups analysed included country and world region. Risk of bias was assessed with the AMSTAR tool and Newcastle-Ottawa Scale. RESULTS: We included 100 reviews and 27 cohort/case-control studies (N = 3 046 661). Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with significant reduction in risk of dementia. When studies examining metformin were divided by country, the only significant effect was for the United States. Moreover, the effect of metformin was significant in Western but not Eastern populations. No significant effect was observed for dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors, or insulin, while meglitinides and sulphonylureas were associated with increased risk. CONCLUSIONS: Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with reduced risk of dementia. More longitudinal studies aimed at determining their relative benefit in different populations should be conducted.

Cross-sectional study of household solid fuel use and renal function in older adults in China.

BACKGROUND: Emerging evidence links outdoor air pollution and declined renal function but the relationship between household air pollution and renal function is not well understood. METHODS: Using cross-sectional data from the multi-provincial INTERMAP-China Prospective Study, we collected blood samples and questionnaire information on stove use and socio-demographic factors. We calculated estimated glomerular filtration rate (eGFR) from serum creatinine to assess renal function. Participants with eGFR <60 mL/min per 1.73 m2 were defined as having chronic kidney disease (CKD) in this analysis. Generalized estimating equations were used to estimate the association of household fuel with renal function and prevalent CKD in models adjusting for confounders. RESULTS: Among the 646 enrolled adults (40-79y; 56% female), one-third exclusively used clean fuel (gas and electric) cookstoves and 11% of northern China participants (n = 49 of 434) used only clean fuel heaters, whereas the rest used solid fuel. In multivariable models, use of solid fuel cookstoves was associated with 0.17 ml/min/1.73 m2 (95% CI: -0.30, 0.64) higher eGFR and 19% (0.86, 1.64) higher prevalence of CKD than exclusive clean fuel use. Greater intensity of solid fuel use was associated with 0.25 ml/min/1.73 m2 (-0.71, 0.21) lower eGFR per 5 stove-use years, though the confidence intervals included the null, while greater current intensity of indoor solid fuel use was associated with 1.02 (1.00, 1.04) higher prevalent CKD per 100 stove-use days per year. Larger associations between current solid fuel use and intensity of use with lower eGFR and prevalent CKD were observed among participants in southern China, those with hypertension or diabetes (eGFR only), and females (CKD only), through these groups had small sample sizes and some confidence intervals included the null. CONCLUSION: We found inconsistent evidence associating household solid fuel use and renal function in this cross-sectional study of peri-urban Chinese adults.

Identifying Targets to Improve the Management of Severe Hypertension in Pregnancy and Postpartum.

OBJECTIVES: To (1) define quality indicators, (2) describe care gaps, and (3) identify process issues in severe hypertension (sustained systolic blood pressure [BP] ≥160 mm Hg or diastolic BP ≥110 mm Hg) management at our tertiary care centre. METHODS: Pregnant and postpartum persons diagnosed with a hypertensive disorder of pregnancy from 2018 to 2019 were identified. A retrospective cohort of patients with severe hypertension was constructed, and data were collected through chart review. Severe hypertension management was assessed according to defined quality indicators. Clinical characteristics were compared between participants with and without time-to-target BP within 60 minutes. Process issues were examined for each severe hypertension occurrence. RESULTS: Of 608 participants with a hypertensive disorder of pregnancy, 90 (15%) experienced severe hypertension. Median time-to-target BP was 76 minutes (interquartile range 47-123 minutes), and target BP (<155/105 mm Hg) was achieved within 60 minutes in 31/90 (34%) participants. Appropriate antihypertensives for severe hypertension were used in 55/90 (61%), and time-to-treatment initiation was within 30 minutes in 42/54 (78%). Chronic hypertension and oral labetalol use were associated with delays in achieving target BP. Process issues related to severe hypertension management included inappropriate treatment (n = 35/90; 39%), failure to recognize severe hypertension as an emergency (n = 21/90; 23%), and delayed treatment initiation (n = 12/54; 22%). CONCLUSION: We defined quality indicators for severe hypertension management. Time-to-target BP within 60 minutes was achieved in a minority of patients, and chronic hypertension was associated with delayed severe hypertension resolution. Process issues in severe hypertension management were described.

Importance of sex and gender in ischaemic stroke and carotid atherosclerotic disease.

Stroke is a leading cause of death and disability worldwide. Women are disproportionately affected by stroke, exhibiting higher mortality and disability rates post-stroke than men. Clinical stroke research has historically included mostly men and studies were not properly designed to perform sex- and gender-based analyses, leading to under-appreciation of differences between men and women in stroke presentation, outcomes, and response to treatment. Reasons for these differences are likely multifactorial; some are due to gender-related factors (i.e. decreased social support, lack of stroke awareness), yet others result from biological differences between sexes. Unlike men, women often present with 'atypical' stroke symptoms. Lack of awareness of 'atypical' presentation has led to delays in hospital arrival, diagnosis, and treatment of women. Differences also extend to carotid atherosclerotic disease, a cause of stroke, where plaques isolated from women are undeniably different in morphology/composition compared to men. As a result, women may require different treatment than men, as evidenced by the fact that they derive less benefit from carotid revascularization than men but more benefit from medical management. Despite this, women are less likely than men to receive medical therapy for cardiovascular risk factor management. This review focuses on the importance of sex and gender in ischaemic stroke and carotid atherosclerotic disease, summarizing the current evidence with respect to (i) stroke incidence, mortality, awareness, and outcomes, (ii) carotid plaque prevalence, morphology and composition, and gene connectivity, (iii) the role of sex hormones and sex chromosomes in atherosclerosis and ischaemic stroke risk, and (iv) carotid disease management.

Current models of apolipoprotein A-I lipidation by adenosine triphosphate binding cassette transporter A1.

PURPOSE OF REVIEW: The primary cardioprotective function of high-density lipoprotein (HDL) is to remove excess cellular free cholesterol (FC) from peripheral tissues and deliver it to the liver. Here, we summarize recent research that examines apolipoprotein A-I (apoA-I) lipidation models by adenosine triphosphate binding cassette transporter A1 (ABCA1) and discuss its relevance in atherosclerotic cardiovascular disease (ASCVD). RECENT FINDINGS: The first step in HDL formation involves the interaction between apoA-I and ABCA1, where ABCA1 mediates the removal of FC and phospholipids from lipid-laden macrophages to form discoidal nascent HDL (nHDL). However, there are currently no clear-cut systematic models that characterize HDL formation. A number of recent studies have investigated the importance of apoA-I C- and N-terminal domains required for optimal cholesterol efflux and nHDL production. Furthermore, functional ABCA1 is required for direct or indirect binding to apoA-I where ABCA1 dimer-monomer interconversion facilitates apoA-I lipidation from plasma membrane microdomains. Microparticles are also another lipid source for apoA-I solubilization into nHDL. SUMMARY: ApoA-I and ABCA1 are key factors in macrophage-mediated cholesterol efflux and nHDL production. Understanding of the key steps in HDL formation may unlock the therapeutic potential of HDL and improve clinical management of ASCVD.

Sleep-disordered breathing in high-risk pregnancies is associated with elevated arterial stiffness and increased risk for preeclampsia.

BACKGROUND: Impaired vascular function is a central feature of pathologic processes preceding the onset of preeclampsia. Arterial stiffness, a composite indicator of vascular health and an important vascular biomarker, has been found to be increased throughout pregnancy in those who develop preeclampsia and at the time of preeclampsia diagnosis. Although sleep-disordered breathing in pregnancy has been associated with increased risk for preeclampsia, it is unknown if sleep-disordered breathing is associated with elevated arterial stiffness in pregnancy. OBJECTIVE: This prospective observational cohort study aimed to evaluate arterial stiffness in pregnant women, with and without sleep-disordered breathing and assess the interaction between arterial stiffness, sleep-disordered breathing, and preeclampsia risk. STUDY DESIGN: Women with high-risk singleton pregnancies were enrolled at 10 to 13 weeks' gestation and completed the Epworth Sleepiness Score, Pittsburgh Sleep Quality Index, and Restless Legs Syndrome questionnaires at each trimester. Sleep-disordered breathing was defined as loud snoring or witnessed apneas (≥3 times per week). Central arterial stiffness (carotid-femoral pulse wave velocity, the gold standard measure of arterial stiffness), peripheral arterial stiffness (carotid-radial pulse wave velocity), wave reflection (augmentation index, time to wave reflection), and hemodynamics (central blood pressures, pulse pressure amplification) were assessed noninvasively using applanation tonometry at recruitment and every 4 weeks from recruitment until delivery. RESULTS: High-risk pregnant women (n=181) were included in the study. Women with sleep-disordered breathing (n=41; 23%) had increased carotid-femoral pulse wave velocity throughout gestation independent of blood pressure and body mass index (P=.042). Differences observed in other vascular measures were not maintained after adjustment for confounders. Excessive daytime sleepiness, defined by Epworth Sleepiness Score >10, was associated with increased carotid-femoral pulse wave velocity only in women with sleep-disordered breathing (Pinteraction=.001). Midgestation (first or second trimester) sleep-disordered breathing was associated with an odds ratio of 3.4 (0.9-12.9) for preeclampsia, which increased to 5.7 (1.1-26.0) in women with sleep-disordered breathing and hypersomnolence, whereas late (third-trimester) sleep-disordered breathing was associated with an odds ratio of 8.2 (1.5-39.5) for preeclampsia. CONCLUSION: High-risk pregnant women with midgestational sleep-disordered breathing had greater arterial stiffness throughout gestation than those without. Sleep-disordered breathing at any time during pregnancy was also associated with increased preeclampsia risk, and this effect was amplified by hypersomnolence.

An LC-MS/MS Methodological Framework for Steroid Hormone Measurement from Human Serum.

Estrogens and androgens are important regulators of sexual development and physiological processes in men and women, acting on numerous organs throughout the body. Moreover, they can contribute to a variety of pathologies, including osteoporosis, cancer, and cardiovascular and neurologic diseases. Analysis of estrogens and androgens in biological samples has been commonly performed using immunoassays for many years. However, these assays are suboptimal, as there is cross-reactivity with similar analytes, and they have moderate specificity and sensitivity. Thus, there is a clinical need to develop highly sensitive and specific methods for the accurate measurement of estrogen and androgen concentrations. Herein, we describe the development of three liquid chromatography coupled tandem mass spectrometry-based methods that incorporate the use of a Triple Quadrupole Mass Spectrometer for quantitative measurement of endogenous concentrations of various steroid hormones in human serum samples: (1) the simultaneous measurement of testosterone, androstenedione, and cortisol, (2) dehydroepiandrosterone (DHEA), and (3) 17ß-estradiol (E2). The use of derivatizing reagents, Girard's reagent P and dansyl chloride, allowed for significant gains in sensitivity in the analysis of DHEA and E2, respectively, relative to the underivatized analyte. These procedures proved efficient and adequately sensitive for steroid hormone analysis in extracted patient sera samples from older men and postmenopausal women, providing reliable data down to low nanogram/ml and sub-nanogram/ml levels. Moreover, utilizing the combination of highly specific mass transitions associated with these analytes and their respective internal deuterated standards provided a high degree of specificity to the identity of these hormones.

Targeting the residual cardiovascular risk by specific anti-inflammatory interventions as a therapeutic strategy in atherosclerosis.

Chronic subclinical inflammation is a key process in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). Along with lipids, inflammation is essential for the initiation and progression of atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine secretion. Several pro-inflammatory cytokines have been described in the primary and secondary prevention of ASCVD. Although extensive work over the past decades has established the role of lipid-lowering medications in the prevention and treatment of ASCVD, modulation of inflammation is a subject of active debate. It remains to be confirmed whether targeting the residual cardiovascular risk by adding anti-inflammatory agents to the conventional cardiovascular treatment becomes a shifting paradigm for ASCVD management. This review aims to discuss novel therapeutic agents targeting inflammatory pathways in ASCVD in light of the canakinumab anti-inflammatory thrombosis outcomes study (CANTOS) trial results. Further we discuss the effects of different anti-inflammatory agents administered in patients with ASCVD and their potential to change clinical practice in preventive cardiology.

Association Between Patient Factors and the Effectiveness of Wearable Trackers at Increasing the Number of Steps per Day Among Adults With Cardiometabolic Conditions: Meta-analysis of Individual Patient Data From Randomized Controlled Trials.

BACKGROUND: Current evidence supports the use of wearable trackers by people with cardiometabolic conditions. However, as the health benefits are small and confounded by heterogeneity, there remains uncertainty as to which patient groups are most helped by wearable trackers. OBJECTIVE: This study examined the effects of wearable trackers in patients with cardiometabolic conditions to identify subgroups of patients who most benefited and to understand interventional differences. METHODS: We obtained individual participant data from randomized controlled trials of wearable trackers that were conducted before December 2020 and measured steps per day as the primary outcome in participants with cardiometabolic conditions including diabetes, overweight or obesity, and cardiovascular disease. We used statistical models to account for clustering of participants within trials and heterogeneity across trials to estimate mean differences with the 95% CI. RESULTS: Individual participant data were obtained from 9 of 25 eligible randomized controlled trials, which included 1481 of 3178 (47%) total participants. The wearable trackers revealed that over the median duration of 12 weeks, steps per day increased by 1656 (95% CI 918-2395), a significant change. Greater increases in steps per day from interventions using wearable trackers were observed in men (interaction coefficient -668, 95% CI -1157 to -180), patients in age categories over 50 years (50-59 years: interaction coefficient 1175, 95% CI 377-1973; 60-69 years: interaction coefficient 981, 95% CI 222-1740; 70-90 years: interaction coefficient 1060, 95% CI 200-1920), White patients (interaction coefficient 995, 95% CI 360-1631), and patients with fewer comorbidities (interaction coefficient -517, 95% CI -1188 to -11) compared to women, those aged below 50, non-White patients, and patients with multimorbidity. In terms of interventional differences, only face-to-face delivery of the tracker impacted the effectiveness of the interventions by increasing steps per day. CONCLUSIONS: In patients with cardiometabolic conditions, interventions using wearable trackers to improve steps per day mostly benefited older White men without multimorbidity. TRIAL REGISTRATION: PROSPERO CRD42019143012; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=143012.

Expression of Resistin, Chemerin, and Chemerin's Receptor in the Unstable Carotid Atherosclerotic Plaque.

Background and Purpose: Unstable carotid plaques are a common cause of ischemic strokes. Identifying markers that reflect/contribute to plaque instability has become a prominent focus in cardiovascular research. The adipokines, resistin and chemerin, and ChemR23 (chemerin receptor), may play a role in carotid atherosclerosis, making them potential candidates to assess plaque instability. However, the expression and interrelationship of resistin and chemerin (and ChemR23) protein and mRNA within the carotid atherosclerotic plaque remains elusive. Thus, we investigated herein, the association between plaque mRNA and protein expression of resistin and chemerin (and ChemR23) and carotid plaque instability in humans, and whether sex differences exist in the relationship between these adipokines and plaque instability. Methods: Human carotid plaques were processed for immunohistochemical/mRNA analysis of resistin, chemerin, and ChemR23. Plaque instability was assessed by gold-standard histological classifications. A semi-quantitative scoring system was used to determine the intensity of adipokine expression on macrophages/foam cells, as well as the percentage of inflammatory cells stained positive. Plaque adipokine protein expression was also digitally quantified and mRNA expression was assessed by qRT-PCR. Results: Resistin and chemerin mRNA expression was 80% and 32% lower, respectively, in unstable versus stable plaques (P<0.05), while no difference in ChemR23 mRNA expression was observed. In contrast, greater resistin staining intensity and percentage of cells stained positive were detected in unstable versus stable plaques (P<0.01). Similarly, chemerin and ChemR23 staining intensity and percentage of cells stained were positively associated with plaque instability (P<0.05). No strong sex-specific relationship was observed between adipokines and plaque instability. Conclusions: This study examined the relationship between resistin, chemerin, and ChemR23, and carotid plaque instability, with a specific analysis at the plaque level. We reported a positive association between plaque instability and protein levels of resistin, chemerin, and ChemR23 but a negative association with resistin and chemerin mRNA expression. This suggests these adipokines exert proinflammatory roles in the process of carotid atherosclerosis and may be regulated via a negative feedback regulatory mechanism.

Alcohol Exerts a Shifted U-Shaped Effect on Central Blood Pressure in Young Adults.

BACKGROUND: Consumption of 1-2 alcoholic beverages daily has been associated with a lower risk of cardiovascular disease and all-cause mortality in middle-aged and older adults. Central blood pressure has emerged as a better predictor of cardiovascular risk than peripheral blood pressure. However, the effects of habitual alcohol consumption on central blood pressure particularly in young adults, who are among the largest consumers of alcohol in North America, have yet to be investigated. OBJECTIVE: We aimed to study the effect of alcohol consumption on central and peripheral blood pressure, and arterial stiffness in young adults. DESIGN: Cross-sectional observational study. MAIN MEASURES: Using a standardized questionnaire, alcohol consumption (drinks/week) was queried; participants were classified as non- (< 2), light (2-6), moderate (women 7-9, men 7-14), and heavy drinkers (women > 9, men > 14). Central blood pressure and arterial stiffness were measured using applanation tonometry. KEY RESULTS: We recruited 153 healthy, non-smoking, non-obese individuals. We found a U-shaped effect of alcohol consumption on blood pressure. Light drinkers had significantly lower central systolic and mean arterial blood pressure, but not peripheral blood pressure when compared to non- and moderate/heavy drinkers (P < 0.05). No significant associations with arterial stiffness parameters were noted. CONCLUSIONS: A U-shaped relationship was found between alcohol consumption and central and mean arterial blood pressure in young individuals, which importantly, was shifted towards lower levels of alcohol consumption than currently suggested. This is the first study, to our knowledge, that examines the effect of alcohol consumption on central blood pressure and arterial stiffness exclusively in young individuals. Prospective studies are needed to confirm the relationships observed herein.

Intensive Statin Therapy Compromises the Adiponectin-AdipoR Pathway in the Human Monocyte-Macrophage Lineage.

Background and Purpose- Statins are widely used for cardiovascular disease prevention through cholesterol-lowering and anti-inflammatory effects. Adiponectin, an anti-inflammatory adipokine, acts via two receptors, AdipoR1 and AdipoR2, to exert atheroprotective effects on the vasculature. We investigated whether statins can modulate the adiponectin-AdipoR pathway in the human monocyte-macrophage lineage. Methods- Monocytes were isolated from the whole blood of patients with severe carotid atherosclerosis (cross-sectional study) or from patients with cardiovascular risk factors (longitudinal study) and assessed for AdipoR1 and AdipoR2 gene expression using quantitative real-time polymerase chain reaction. In vitro, THP-1 (Tamm-Horsfall protein 1) macrophages were treated with increasing atorvastatin or rosuvastatin doses for 24- or 72-hours to determine the effect of statins on AdipoR expression and activity. Macrophage cytokine secretion (IL [interleukin]-1ß, IL-10, IL-6, and TNF [tumor necrosis factor]-α) was assessed by electrochemiluminescence. Results- AdipoR1 and AdipoR2 mRNA expression on circulating monocytes from patients with carotid atherosclerosis, was significantly lower by 1.36- and 1.17-fold, respectively, in statin users versus statin-naïve patients. Specifically, patients on high doses of atorvastatin (40-80 mg) or rosuvastatin (20-40 mg) had significantly lower AdipoR gene expression versus statin-naïve patients. Similarly, in the longitudinal in vivo study, longer atorvastatin/rosuvastatin treatment (≥5 months) in patients with cardiovascular risk factors resulted in lower AdipoR gene expression on circulating monocytes versus prestatin levels. In vitro, higher statin doses and longer exposure resulted in a greater decrease in AdipoR mRNA expression and greater macrophage secretion of pro-inflammatory cytokines, IL-1ß, IL-6, and TNF-α. High statin doses also reduced adiponectin's capacity to suppress intracellular cholesteryl ester levels in oxLDL (oxidized LDL)-loaded macrophages, with rosuvastatin exhibiting higher potency than atorvastatin. Conclusions- Our in vivo and in vitro studies identified a novel pleiotropic property of statins in modulating the adiponectin-AdipoR pathway in the human monocyte-macrophage lineage, where intensive statin therapy compromised the expression and function of adiponectin and its receptors.

New Quantitative Digital Image Analysis Method of Histological Features of Carotid Atherosclerotic Plaques.

OBJECTIVE: Atherosclerosis and its thrombotic complications are major causes of morbidity and mortality worldwide. Plaque stability assessment is considered to be important for both clinical and fundamental applications. The current gold standard method to investigate plaque stability is performed by histological assessment of plaque features using semi-quantitative classifications. However, these assessments can be limited by subjectivity and variability. Thus, the aim was to develop a new digital image analysis method to measure quantitatively individual plaque features that is more precise than existing semi-quantitative methods. METHODS: A quantitative method was developed using Image Pro Primer software. Carotid plaque specimens were obtained from patients who underwent carotid endarterectomy and categorised according to stability (definitely stable, probably stable, probably unstable, definitely unstable) based on the gold standard semi-quantitative method that assesses 10 histological plaque features. Using the new quantitative method, plaque features (n = 15) from each stability grade were then analysed by two independent raters. For the semi-quantitative analysis, quadratic weighted Cohen's kappa was used to test intra- and inter-rater reliability, while for the quantitative analysis, intraclass correlation coefficients (ICCs) were assessed. RESULTS: Intra-rater reliability demonstrated almost perfect agreement between both methods (Cohen's kappa range 0.831-0.969, ICC range 0.848-1.000). However, inter-rater reliability demonstrated mainly fair to moderate agreement (Cohen's kappa range 0.341-0.778) for the semi-quantitative analysis, while the digital image analysis method performed most optimally regarding reproducibility, yielding high ICCs close to 1 (ICC range 0.816-0.999). Using quantitative measurements, a statistically significant proportion of the individual plaque features (p < .05) were re-classified from one grade to another (shift by one) under the semi-quantitative classification. CONCLUSION: A new quantitative digital image analysis was developed for the accurate assessment of histological plaque features, which demonstrated higher precision than the gold standard semi-quantitative methods, as measured by between and within rater analysis. Moreover, quantitative image analysis of histological plaque features provided more detailed insight into plaque morphology and composition.

Longitudinal evaluation of a household energy package on blood pressure, central hemodynamics, and arterial stiffness in China.

BACKGROUND: Cardiovascular diseases are the leading contributors to disease burden in China and globally, and household air pollution exposure is associated with risk of cardiovascular disease. OBJECTIVES: We evaluated whether subclinical cardiovascular outcomes in adult Chinese women would improve after distribution of an energy package comprised of a semi-gasifier cookstove, water heater, chimney, and supply of processed biomass fuel. METHODS: We enrolled 204 households (n = 205 women) from 12 villages into a controlled before- and after-intervention study on cardiovascular health and air pollution in Sichuan Province. The intervention was distributed to 124 households during a government-sponsored rural energy demonstration program. The remaining 80 households received the package 18 months later at the end of the study, forming a comparison group. One woman from each household had their blood pressure (BP), central hemodynamics, and arterial stiffness measured along with exposures to air pollution and demographic and household characteristics, on up to five visits. We used a difference-in-differences mixed-effects regression approach with Bayesian inference to assess the impact of the energy package on sub-clinical cardiovascular outcomes. RESULTS: Women who did not receive the energy package had greater mean decreases in brachial systolic (-4.1 mmHg, 95% credible interval (95%CIe) -7.3, -0.9) and diastolic BP (-2.0 mmHg, 95%CIe -3.6, -0.5) compared with women who received the package (systolic: -2.7, 95%CIe -5.0, -0.4; diastolic: -0.3, 95%CIe -1.4, 0.8) resulting in slightly positive but not statistically significant difference-in-differences effect estimates of 1.3 mmHg (95%CIe -2.5, 5.2) and 1.7 mmHg (95%CIe -0.3, 3.6), respectively. Similar trends were found for central BP, central pulse pressure, and arterial stiffness. Air pollution exposures decreased on average for both treatment groups, with a greater range of reductions among women who did not receive the package (with package: -30% to -50%; without package: +2% to -69%), likely as a result of increased use of gas fuel and electric stoves among this group. Outdoor air quality changed very little over time. CONCLUSIONS: Gasifier stoves have been widely promoted as the next generation of 'clean-cooking' technologies, however their effectiveness in improving health in real-world settings should be carefully evaluated and communicated before scaling up their implementation.

Decreased Adiponectin-Mediated Signaling Through the AdipoR2 Pathway Is Associated With Carotid Plaque Instability.

BACKGROUND AND PURPOSE: Adiponectin, the most abundantly secreted anti-inflammatory adipokine, protects against all stages of atherosclerotic plaque formation by acting on its receptors, AdipoR1 (adiponectin receptor 1) and AdipoR2 (adiponectin receptor 2). Through binding of AdipoR1, adiponectin leads to the activation of the AMPK (adenosine monophosphate-activated protein kinase) pathway, whereas stimulation of PPAR-α (peroxisome proliferator-activated receptor-α) is attributed to the binding of AdipoR2. However, the role of adiponectin and its receptors in plaque instability remains to be characterized. Thus, we aimed to investigate whether the adiponectin-AdipoR pathway is associated with carotid atherosclerotic plaque instability. METHODS: The instability of plaque specimens obtained from patients who underwent a carotid endarterectomy (n=143) was assessed using gold standard histological classifications. RESULTS: Using immunohistochemistry, we showed that adiponectin and AdipoR1/AdipoR2 are expressed in human carotid plaques and that their expression was localized most abundantly in areas of macrophage and foam cell accumulation. Unstable plaques expressed more adiponectin protein (Western blot, P<0.05) and less AdipoR2 mRNA (2.11-fold decrease, P<0.05) than stable plaques, whereas AdipoR1 expression remained similar between stable and unstable plaques. Beyond AdipoR1/AdipoR2 expression, a graded decrease in PPAR-α protein levels was observed in relation to carotid plaque instability (P<0.001), whereas AMPK phosphorylation was increased (P<0.05). Our in vitro model of plaque instability, involving the induction of foam cells from human THP-1 (Tamm-Horsfall protein 1) macrophages treated with acetylated low-density lipoprotein, supported our in vivo conclusions. CONCLUSIONS: An overall abundance of adiponectin with a decrease in AdipoR2 expression and activity was observed in unstable plaques, suggesting that reduced signaling through the AdipoR2 pathway, and not through AdipoR1, may contribute to plaque instability.

Physician step prescription and monitoring to improve ARTERial health (SMARTER): A randomized controlled trial in patients with type 2 diabetes and hypertension.

AIMS: There are few proven strategies to enhance physical activity and cardiometabolic profiles in patients with type 2 diabetes and hypertension. We examined the effects of physician-delivered step count prescriptions and monitoring. METHODS: Participants randomized to the active arm were provided with pedometers and they recorded step counts. Over a 1-year period, their physicians reviewed their records and provided a written step count prescription at each clinic visit. The overall goal was a 3000 steps/day increase over 1 year (individualized rate of increase). Control arm participants were advised to engage in physical activity 30 to 60 min/day. We evaluated effects on step counts, carotid femoral pulse wave velocity (cfPWV, primary) and other cardiometabolic indicators including haemoglobin A1c in diabetes (henceforth abbreviated as A1c) and Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) in participants not receiving insulin therapy. RESULTS: A total of 79% completed final evaluations (275/347; mean age, 60 years; SD, 11). Over 66% of participants had type 2 diabetes and over 90% had hypertension. There was a net 20% increase in steps/day in active vs control arm participants (1190; 95% CI, 550-1840). Changes in cfPWV were inconclusive; active vs control arm participants with type 2 diabetes experienced a decrease in A1c (-0.38%; 95% CI, -0.69 to -0.06). HOMA-IR also declined in the active arm vs the control arm (ie, assessed in all participants not treated with insulin; -0.96; 95% CI, -1.72 to -0.21). CONCLUSIONS: A simple physician-delivered step count prescription strategy incorporated into routine clinical practice led to a net 20% increase in step counts; however, this was below the 3000 steps/day targeted increment. While conclusive effects on cfPWV were not observed, there were improvements in both A1c and insulin sensitivity. Future studies will evaluate an amplified intervention to increase impact.

Circulating Chemerin Is Associated With Carotid Plaque Instability, Whereas Resistin Is Related to Cerebrovascular Symptomatology.

OBJECTIVE: The rupture of unstable carotid atherosclerotic plaques is one of the main causes of cerebrovascular ischemic events. There is need for circulating markers that can predict plaque instability and risk of stroke. Proinflammatory chemerin, leptin, and resistin, along with anti-inflammatory adiponectin, are adipokines with direct influence on vascular function. We investigated the association of circulating adipokines with carotid plaque instability and cerebrovascular symptomatology. APPROACH AND RESULTS: Neurologically symptomatic and asymptomatic patients (n=165) scheduled for carotid endarterectomy were recruited. Fasting blood samples were collected preoperatively; adiponectin and leptin levels were determined by radioimmunoassay; and chemerin and resistin levels were measured by enzyme-linked immunosorbent assays. The instability of plaque specimens was assessed using gold-standard histological classifications. Chemerin was significantly associated with plaque instability. The fully adjusted model, accounting for age, sex, body mass index, high-sensitivity C-reactive protein, type 2 diabetes mellitus, and circulating adiponectin, leptin, and resistin, yielded an odds ratio of 0.991 (95% confidence interval 0.985-0.998) for plaque instability per unit increase in chemerin. High leptin levels were significantly associated with presence of specific features of plaque instability. In subjects with type 2 diabetes mellitus, resistin levels were significantly elevated in symptomatic when compared with asymptomatic subjects (P=0.001) and increased the risk of cerebrovascular symptomatology (adjusted odds ratio 1.264, 95% confidence interval 1.004-1.594). CONCLUSIONS: Low chemerin and high resistin levels were associated with carotid disease severity, suggesting that these adipokines may act as potential markers for plaque instability and stroke risk. Future studies are needed to assess causation between circulating adipokines and plaque instability.